Elsevier

The Lancet

Volume 389, Issue 10072, 4–10 March 2017, Pages 930-939
The Lancet

Articles
High-flow warm humidified oxygen versus standard low-flow nasal cannula oxygen for moderate bronchiolitis (HFWHO RCT): an open, phase 4, randomised controlled trial

https://doi.org/10.1016/S0140-6736(17)30061-2Get rights and content

Summary

Background

Bronchiolitis is the most common lung infection in infants and treatment focuses on management of respiratory distress and hypoxia. High-flow warm humidified oxygen (HFWHO) is increasingly used, but has not been rigorously studied in randomised trials. We aimed to examine whether HFWHO provided enhanced respiratory support, thereby shortening time to weaning off oxygen.

Methods

In this open, phase 4, randomised controlled trial, we recruited children aged less than 24 months with moderate bronchiolitis attending the emergency department of the John Hunter Hospital or the medical unit of the John Hunter Children's Hospital in New South Wales, Australia. Patients were randomly allocated (1:1) via opaque sealed envelopes to HFWHO (maximum flow of 1 L/kg per min to a limit of 20 L/min using 1:1 air–oxygen ratio, resulting in a maximum FiO2 of 0·6) or standard therapy (cold wall oxygen 100% via infant nasal cannulae at low flow to a maximum of 2 L/min) using a block size of four and stratifying for gestational age at birth. The primary outcome was time from randomisation to last use of oxygen therapy. All randomised children were included in the primary and secondary safety analyses. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12612000685819.

Findings

From July 16, 2012, to May 1, 2015, we randomly assigned 202 children to either HFWHO (101 children) or standard therapy (101 children). Median time to weaning was 24 h (95% CI 18–28) for standard therapy and 20 h (95% CI 17–34) for HFWHO (hazard ratio [HR] for difference in survival distributions 0·9 [95% CI 0·7–1·2]; log rank p=0·61). Fewer children experienced treatment failure on HFWHO (14 [14%]) compared with standard therapy (33 [33%]; p=0·0016); of these children, those on HFWHO were supported for longer than were those on standard therapy before treatment failure (HR 0·3; 95% CI 0·2–0·6; p<0·0001). 20 (61%) of 33 children who experienced treatment failure on standard therapy were rescued with HFWHO. 12 (12%) of children on standard therapy required transfer to the intensive care unit compared with 14 (14%) of those on HFWHO (difference −1%; 95% CI −7 to 16; p=0·41). Four adverse events occurred (oxygen desaturation and condensation inhalation in the HFWHO group, and two incidences of oxygen tubing disconnection in the standard therapy group); none resulted in withdrawal from the trial. No oxygen-related serious adverse events occurred. Secondary effectiveness outcomes are reported in the Results section.

Interpretation

HFWHO did not significantly reduce time on oxygen compared with standard therapy, suggesting that early use of HFWHO does not modify the underlying disease process in moderately severe bronchiolitis. HFWHO might have a role as a rescue therapy to reduce the proportion of children requiring high-cost intensive care.

Funding

Hunter Children's Research Foundation, John Hunter Hospital Charitable Trust, and the University of Newcastle Priority Research Centre GrowUpWell.

Introduction

High-flow warm humidified oxygen (HFWHO)—also known as high-flow nasal cannula oxygen—in paediatric health care has been investigated in the contexts of neonatal1 and paediatric intensive care units (ICUs),2, 3 but its safety and efficacy in children have not been established by randomised trials.4, 5 In the neonatal context, a non-inferiority study1 of HFWHO at 5–8 L/min found the efficacy of HFWHO to be similar to continuous positive airway pressure (CPAP), and a randomised controlled trial6 showed no difference in the rate of extubation failure between HFWHO and CPAP.

Adult studies7, 8 of HFWHO have also found no difference in various primary outcomes. Intubation rates did not differ in a study7 of HFWHO versus standard non-rebreather mask oxygen or a combination of non-invasive ventilation and HFWHO in patients with hypoxaemia, but a reduced 90-day mortality was noted in favour of HFWHO. Another study8 found HFWHO to be non-inferior to bilevel positive airway pressure in preventation of treatment failure after cardiothoracic surgery.

Although observational studies9, 10 and retrospective audits2, 3 suggest promising outcomes from the use of HFWHO in paediatric care, large randomised trials are needed to provide evidence of superior safety and efficacy.4, 5, 11, 12 A Bangladeshi randomised trial13 (n=225) compared CPAP, 2 L/kg per min high-flow oxygen, and standard therapy in children aged less than 5 years with severe pneumonia, but was stopped early due to increased mortality in the standard therapy group (ten deaths) compared with the CPAP group (three deaths).

Research in context

Evidence before this study

We searched PubMed and MEDLINE for clinical trials published in English between Jan 1, 2000, and July 1, 2016, using the terms “high-flow oxygen”, “infants”, “children”, “p*ediatrics”, “bronchiolitis”, but could not find randomised trial evidence for the use of high-flow oxygen compared to standard low-flow nasal cannula oxygen. We identified a randomised trial (n=19) comparing variable flow oxygen (4–8 L/min) with headbox oxygen in bronchiolitis through Beggs and colleagues' Cochrane review, whereas Mayfield and colleagues' review examining high-flow oxygen in any paediatric context other than bronchiolitis found none. A recent Bangladeshi trial (n=225) compared CPAP, 2 L/kg per min high-flow oxygen, and standard therapy in children with severe pneumonia, but was stopped early because of the significant benefit of CPAP over standard therapy for mortality (three deaths vs ten deaths). Paediatric observational studies and audits suggest that high-flow oxygen is beneficial, and Manley and colleagues were able to show equivalence to CPAP post-extubation of neonates. However, other studies in neonates and adults have found no difference in their primary outcome.

Added value of this study

To our knowledge, this study is the first randomised trial to examine HFWHO in a paediatric, ward-based cohort. HFWHO and standard therapy were both effective when standardised approaches to starting and weaning oxygen were used, and early use of HFWHO did not alter the overall course of the bronchiolitis. HFWHO prevented clinical deterioration in significantly more infants than standard therapy and was able to reverse deterioration in 63% (95% CI 45–77) of the 32% (23–41) of those who were not adequately supported by standard therapy.

Implications of all the available evidence

For children with moderate bronchiolitis, HFWHO is safe and effective at 1 L/kg per min (maximum FiO12 0·6). For children who are not supported by standard therapy, HFWHO might reduce the need for admission to ICU with substantial cost savings. Whereas observational studies have suggested that HFWHO is more beneficial compared with standard therapy, our study has not shown superiority for the primary endpoint of time on oxygen. Future research is required to test HFWHO as a rescue treatment in bronchiolitis, to test its application to other paediatric respiratory conditions, and to examine the safety and effectiveness of standardised procedures for starting and weaning of oxygen with economic outcomes.

CPAP=continuous positive airway pressure. HFWHO=high-flow warm humidified oxygen.

To address the insufficiency of evidence surrounding the safety and effectiveness of high-flow oxygen in paediatric health care, we conducted a pragmatic randomised controlled trial14 designed to provide clinical guidance for the care of children with moderate bronchiolitis hospitalised for supplemental oxygen therapy. Bronchiolitis is a major contributor to paediatric and intensive-care admission rates each year. With only supportive treatment options available15, 16, 17 and a mortality rate in children aged under 5 years estimated at 199 000 per year globally for respiratory syncytial virus (RSV) alone,16 a large proportion of children with bronchiolitis rely on the optimal delivery of supplemental oxygen as mainstay therapy.

The aim of our study was to examine whether HFWHO provided enhanced respiratory support as evidenced by a reduction in time to weaning off oxygen, hypothesising that HFWHO might increase the alveolar surface area, improve ventilation–perfusion mismatch, and reduce ventilation inhomogeneities.

Section snippets

Study design

We conducted an open, phase 4, randomised controlled trial from July 16, 2012, to May 1, 2015, in the emergency department of the John Hunter Hospital and the medical unit of the John Hunter Children's Hospital in the Hunter New England Local Health District of New South Wales (NSW), Australia. This health district has a catchment area similar in size to England and serves approximately 900 000 people. The John Hunter Children's Hospital is co-located with the adult John Hunter Hospital and is

Results

From July 16, 2012, to May 1, 2015, 1170 children aged less than 24 months presented to the emergency department with a primary diagnosis of bronchiolitis and 753 were admitted for management (figure 1). Of those admitted, 449 had moderate bronchiolitis requiring supplemental oxygen and 395 were eligible for inclusion in the study, with 54 ineligible due to being transferred from other sites with oxygen in progress. Parents of 12 children declined consent. 202 children were randomly assigned to

Discussion

In this single-centre, open, randomised controlled trial, we found no evidence of a difference in the survival distributions for time to weaning off oxygen between HFWHO and standard therapy for children aged less than 24 months with moderate bronchiolitis. This primary outcome was inclusive of treatment failure and any time spent in ICU, and crossover to HFWHO was included in both the ITT and per-protocol analyses. We found statistically significant and clinically important effects of HFWHO in

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